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Introduction  

GABAergic inhibition is essential for controlling cell excitability,
maintaining the excitatory/inhibitory balance of neuronal circuits and
determining the input and output relationship of neurons. Disruption of this
balance due to changes in GABAA receptor(GABAAR)
trafficking has been increasingly associated in neurological and
neurodegenerative diseases including epilepsy, stroke and Huntington’s disease
(HD). Many studies have indicated a change in excitatory synaptic activity.
Conversely, studies have also indicated an increase in inhibitory GABAergic
synaptic activity. This review essay aims to focus on the changes in inhibitory
neurotransmission in Huntington’s disease. The essay will first address the
mechanism by which Huntington’s disease is known to occur and how inhibitory
transmission is affected by this disorder. Evidence illustrating these changes
in inhibitory transmission in Huntington’s disease will be shown in animal
(mice) studies12.

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Huntington’s Disease

Huntington’s
disease is a genetic mutation where an unstable expansion of CAG trinucleotide
repeat is found within the coding region of the HD (Htt) gene. It is located on
the short arm of chromosome 4 (4p63) and encodes the protein huntingtin. The
main clinical symptom of the disease is the occurrence of involuntary movements
which is a result of loss of function of the medium spiny neurons(MSNs) in the
striatum other symptoms include cognitive and psychiatric alterations.
Moreover, the disease is progressive and can invariably lead to death. The
genetic mutation of HD has shown to have a role in GABAAR
transportation. GABAAR are assembled in the endoplasmic
reticulum(ER) and led through the secretory pathway by receptor associated
proteins. Once inserted into the membrane, receptors diffuse and become attached
at post-synaptic sites through association with gephyrin. GABAARs
are endocytosed at synaptic sites and these GABAARs then undergo a sorting
decision as to whether it should be recycled back to the membrane or be
ubiquitinated and targeted for lysosomal degradation. This sorting decision is
regulated by the Huntingtin-associated protein 1 (HAP1) that interacts with
GABAAR b subunits and by ubiquitination of g2
subunits. By linking GABAAR containing transport vesicles to a
kinesin superfamily member 5 (KIF5) motor protein complex, HAP1 facilitates the
fast delivery of GABAARs to synapses (Figure 1). However, in an HD
model, mutant polyQ-htt blocks the function of HAP1- KIF5 complex which leads
to a disruption in the trafficking of GABAAR transport vesicles. The
consequences of this block results in a reduced delivery, therefore a reduced
synaptic strength and a reduction in the number of GABAARs at
inhibitory synapses. While cellular and synaptic dysfunction is seen in early
deficits of the disease, neuronal cell death brings about many of the later
symptoms of HD.  PolyQ-Htt presents a
high chance to misfold and aggregate, which leads to the formation of nuclear
inclusions and eventually causes neuronal cell death. Intracellular
accumulation of the ubiquitinated proteins in nuclear inclusions can also lead
to inhibition of protein degradation inducing neuronal cell death134.
This mechanism can be used to explain the observations made by the following
experiments.

 

 

Evidence of changes in inhibitory neurotransmission

An experiment was
conducted to determine alterations in striatal synaptic transmission in 3 mouse
models. The R6/2 mouse model which expresses a truncated transgene consisting
exon 1 with ~150 CAG repeats, the second model, YAC128, carries the full HD
gene on a yeast artificial chromosome and finally the third model, knock-in
mouse CAG140, expressing the mutant HD gene in the normal context of the mouse
genome. In this experiment, spontaneous EPSCs and IPSCs were observed to show
the progressive decrease in excitation and decrease in inhibition in MSNs.
Whole-cell patch-clamp recordings were made to do this. The results of the
spontaneous IPSCs are shown below in Figure 25.

 

 

 

 

As seen in figure
2, the alterations in the GABAergic currents suggest abnormal synaptic
transmission that may be occurring due to the dysfunctional GABAergic
interneurons caused by HD. The research also showed that MSNs from YAC128 had a
higher proportion of cells that responded to GABA receptor blockade with an
increased frequency which was also observed in 12month CAG140 mice. Moreover,
IPSC frequency increased in the youngest age group of YAC128 and a trend of an
increase in IPSC seen in R6/2 mice suggesting an alteration in inhibitory inputs
in the striatum. The study concluded that the YAC128 and CAG140 display similar
striatal electrophysiological phenotypes i.e. the increase in IPSCs, are a
resultant of the mutant polyQ-htt blocking the function of HAP1- KIF5 complex
which leads to a disruption in the trafficking of GABAAR transport
vesicles5.

 

Another study was
conducted to find alterations in excitatory and inhibitory inputs to cortical
pyramidal neurons in HD mouse models. Results taken from this experiment
indicated an increased excitatory drive in all mouse models. Furthermore, the
blockade of GABAA receptors led to an increased frequency of EPSCs
indicating that the cortical pyramidal neurons are inhibited in a greater
degree in HD mice than wild type. Results also showed a delay in GABA current
desensitization and difference in zolpidem modulation. Later progression of the
HD in models showed a reduced expression of GAT1 indicating that there may be a
variation in clearance of the synaptic cleft6. This experiment
shows that the excitatory inputs to pyramidal neurons are enhanced while,
inhibitory inputs are reduced is in the opposite direction with alterations
observed in the striatum as disease progresses.

 

A
further study was conducted using Q175 mouse model which focused on the
electrophysiological alterations in striatal MSNs and CPNs (cortical pyramidal
neurons). The Q175 model was derived from a spontaneous germline CAG expansion
from the CAG140 KI mice, carrying the human mHtt gene containing 140 repeats of
the CAG tract. Findings of this experiment indicate a significant decrease in
excitatory inputs to MSNs at both 7 and 12 months. This was combined with a concurrent
increase in inhibitory inputs and were more distinct in Q175+/- and
Q175+/+ mice. CPNs also showed an increased input of inhibition.
These changes indicate an imbalance in ratio between inhibition and excitation.
sIPSCs frequency in MSNs were also significantly increased as early as 2
months. The study concluded that properties of HD could be seen in these Q175
mice. More significantly, the experiment indicated a loss of excitatory inputs
to MSNs and an increase in inhibitory inputs to CPNs which are congruent with
the changes that occur in the basic striatal microcircuit found in HD as seen
in Figure 3. The figure illustrates the alterations in excitatory and
inhibitory changes in the striatum and cortex. In early HD, there is an
increase in inhibitory input with little change in excitatory input to
pyramidal neurons. If inhibitory input is blocked as in HD, there is an associated
increase in excitation7.

 

 

Although the studies mentioned here coincide with the theory
that strength of the GABAergic inhibition in the striatum increases with
progression of Huntington’s disease, another study conducted using quantal
analysis with high frequency stimulation and paired pulse tests found that synaptic
GABA release is tonically suppressed, resulting in disinhibition of striatal
output activity. It was observed that striatal output neurons displayed lower
amplitudes of evoked inhibitory currents (eIPSCs) and higher frequency levels
of spontaneous inhibitory postsynaptic currents (sIPSCs) than found in WT. The
final results of this study revealed that the increase in sIPSC frequency in HD
is a disinhibitory occurrence due to deficit in GABA synaptic release. This new
evidence suggests a form a glutamate-induced suppression of inhibition to
regulate the balance between glutamate levels and strength of GABA release. The
mechanism that may underlie this effect is the tonic activity of the metabotropic
glutamate receptor (mGluR5) and cannabinoid type 1 receptor mediated depression
of synaptic GABA release. This mechanism can be a consequence of impaired
astrocytic glutamate uptake leading to the activation of mGluR5 which activates
eCB (endocannabinoid) and finally causing a reduced synaptic GABA release
(Figure 4)9.

 

 

 

 Conclusion

The aim
of this essay was to review the various mechanisms that causes alterations in
inhibitory transmission in Huntington’s disease. The genetic mutation of
Huntington’s disease where an unstable expansion of CAG trinucleotide repeat is
found within the coding region of the HD (Htt) gene has found to have a
significant role in GABAAR transportation. This disruption in the
trafficking of GABAAR transport vesicles, results in a reduced delivery,
therefore reducing synaptic strength and a reducing the number of GABAARs
at inhibitory synapses. Evidence supporting this has been shown in several
experiments. Moreover, tonic activity of the metabotropic glutamate receptor
(mGluR5) and cannabinoid type 1 receptor mediated depression of synaptic GABA
release has been observed in the experiment conducted by Dvorzhak. A et al.
understanding the underlying mechanisms of inhibitory as well as excitatory
alterations in transmission can help provide therapeutic targets for treatment
of Huntington’s disease.

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